Project Summary/Abstract Stem cells of adult tissues must coordinate repair and regeneration of their host organs over the course of a lifetime. This presents the unique challenge to robustly produce healthy progeny while avoiding oncogenic growth. In order to manage these potentially opposing needs, stem cells must tightly control their proteome to maintain a stable identity during times of both quiescence and proliferation. Translational regulation has emerged as a key node of proteome regulation, and the integrated stress response (ISR) is an evolutionarily conserved pathway that regulates translation in response to various stresses. The ISR consists of four stress- responsive kinases that phosphorylate eIF2? to decrease global protein synthesis while paradoxically increasing translational efficiency of genes meant to help cope with stress. Increasing evidence suggests that stem cells may harness the ISR to control translation in a way that promotes their function, but little is known about the contexts or consequences of the pathway's activity in healthy or oncogenic stem cells. This proposal sets out an investigation into the role of this pathway in stem cells of the murine epidermis, seeking insight into the role of this pathway for stem cell maintenance during homeostasis, wound-repair, and cancer. First, ISR activity will be measured to determine the contexts in which the pathway becomes activated during these contexts. Next, genetically targeting key regulatory nodes of this pathway in vivo will provide information into the consequences of this pathway's activity in homeostasis and cancer. Understanding the potentially differing roles of this pathway in tissue homeostasis and cancer will provide the information necessary for future strategies to target this pathway in a way that will maximize anti- cancer efficacy while limiting side-effects. This project is an ideal thesis project for a physician-scientist in training, as it plans an investigation into a field with dual needs for both fundamental and clinical advancement. Prior research into the integrated stress response has established this pathway as a key regulator of cellular responses to various stressors, but major questions remain of how this pathway functions in health and disease. The training plan set out in this proposal is organized to integrate basic science and clinical training during all steps of the applicant's education. The environment is ideal for the proposed research and training plan as the Rockefeller University and the Tri-Institutional MD-PhD Program will provide many opportunities to interface with physician-scientist role models. The overarching goal of this proposed investigation into the ISR in homeostasis and cancer is to establish a mentored-training project that will contribute to cancer research while enhancing the applicant's integrated training in the varied skills necessary for success as a physician-scientist.